Severe infections during early childhood are linked to autism — at least in some boys, a new study in mice and people suggests. The findings were published today in Science Advances.

Researchers analyzed the health records of millions of children in the United States and found that boys diagnosed with autism are more likely than non-autistic boys to have had an infection requiring medical attention between age 1 and a half and 4.

The study also showed that provoking a strong immune response in newborn mice with only one copy of TSC2, a gene tied to autism, leads to social memory problems in adult male rodents. In people, mutations in TSC2 cause tuberous sclerosis, a condition characterized by non-cancerous tumors and skin growths. About half of all people with tuberous sclerosis also have autism.

“If the TSC2 mutation was sufficient to cause autism, then everyone with that mutation would have autism — but they don’t,” says senior investigator Alcino Silva, director of the Integrative Center for Learning and Memory at the University of California, Los Angeles.

A child’s chances of having autism rise with severe infections in the child or his mother, previous studies show, but not all children who contract serious infections go on to be diagnosed with autism.

The new study is the first to examine the relationship between immune activation and a specific genetic variant tied to autism, Silva says. The findings suggest that genetics and severe infection represent a ‘two-hit’ scenario for autism.

The work also highlights the importance of vaccinating children, says Manuel López Aranda, a postdoctoral fellow in Silva’s lab.

“If it’s true that serious infections predispose kids to neuropsychiatric conditions, the best way to avoid serious infections in kids is to vaccinate them,” he says.

Immune activation:

Silva, López Aranda and their colleagues injected newborn mice missing a copy of TSC2 with a compound that mimics a viral infection. When isolated from their mothers, the pups squeaked with shorter and simpler call sequences than did control pups, the researchers found. This simplified call repertoire may parallel early social communication difficulties in people with autism.

As adults, the male TSC2 mice seemed to have trouble recognizing and remembering other mice: They did not show the typical preference for spending time with a mouse they had never met before, but they did prefer a novel object over a familiar one.

An analysis of gene expression in three brain areas involved in social behavior suggested that, compared with controls, the male TSC2 mice injected with the viral mimic had increased levels of an immune molecule called interferon, which immune cells release to fight off viruses. The injection also activated microglia, immune cells in the brain that produce interferon and help to shape neuronal connections.

Sex differences in microglial number and function may explain why the immune activation led to social memory problems only in the male TSC2 mice, López Aranda says. The finding is in line with the observation that autism is about four times more prevalent in boys than it is in girls.

Depleting microglia or deleting the receptors for interferon rescued the animals’ social memory problems. Giving the mice a drug called rapamycin, which is in trials for treating tuberous sclerosis, counteracted their strong immune activation and also relieved their social memory problems. Rapamycin acts by suppressing mTOR, a signaling pathway that is overactive in tuberous sclerosis and in response to viral infections.

To investigate whether immune activation in early childhood could be linked to social and other behavioral difficulties in people, the researchers looked at the insurance claims of more than 3.5 million children across the U.S. Of these, 4,417 girls and 18,232 boys had been diagnosed with autism. Autistic boys had a 40 percent increased likelihood of having contracted an infection requiring medical attention between the ages of 1 and half and 4 years, the researchers found.

Two-hit model:

Many researchers have long focused on either genetic or environmental factors that could contribute to autism. By looking at the interplay of both, the new study is “a breath of fresh air,” says Mauro Costa-Mattioli, professor of neuroscience at Baylor College of Medicine in Houston, Texas, who was not involved in the research.

The results of the animal experiments provide a mechanism by which immune response to viral infection could lead to some autism-like traits, Costa-Mattioli says. However, he cautions that the analysis of medical records reveals only an association between severe infection and autism diagnosis. This doesn’t mean that the viral infection cause the behavioral difficulties associated with autism, he says.

It’s also possible that the boys who contracted a serious infection and went on to be diagnosed with autism have genetic mutations linked to autism, says Eric Klann, director of the Center for Neural Science at New York University, who was not involved in the study. If that was true, Klann says, it would support the ‘two-hit’ hypothesis that the interaction between genes and the environment can increase autism risk.

The work may also have clinical implications in that it indicates that rapamycin eases the detrimental effects a strong immune activation may have on social skills, Silva says.

“Of course, this needs to be tested and demonstrated in humans,” he says, “but our work suggests that it may just be possible.”

Cite this article: https://doi.org/10.53053/MQUR6777

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Calling all autism researchers: How are you approaching upcoming conferences and meetings, such as the annual Society for Neuroscience meeting this November, which will be held both virtually and in person? Are you eager to get back to in-person gatherings? Are face-to-face encounters critical to advancing your work? Or are you hesitant to travel? Enjoying the convenience of conferencing from home? Waiting to decide?

Spectrum is working on a story about scientists’ conference plans through the end of this year. The coronavirus pandemic has dramatically altered how scientists share their work — with some effects that may reverberate for years to come. Please help us report this story by taking a short survey about your plans and decision-making process.

The post <em>Spectrum</em> survey: Attending scientific conferences and meetings appeared first on Spectrum | Autism Research News.

Welcome to this month’s edition of the By the Numbers Newsletter. At Spectrum, we do our best to summarize the latest autism research findings — and sometimes the best summary comes in the form of a chart or map. In this newsletter, we boil down interesting new research that is conveyed most succinctly by way of data visualizations.

Let us know what you think of the newsletter, or tell us about your own data-rich work, at niko@spectrumnews.org.

Machine learning and neuroimaging

Machine-learning models may be better at spotting signs of autism in brain scans if the datasets include women, according to a new analysis of data from 44 studies.

“We want to improve the data that is used for machine learning because, you know, ‘garbage in, garbage out,’” says lead investigator Sotirios Bisdas, a neuroradiologist at the National Hospital for Neurology in London, England. The goal of the new study, Bisdas says, was “to understand whether there are systemic biases that affect the data quality and, downstream, may affect results.”

The answer, it turned out, is yes: Some types of neuroimaging data, such as electroencephalography, are potentially better than others for training machine-learning models to identify autism, the study shows. Including women and data from multiple imaging technologies may also improve the sensitivity and specificity of some machine-learning algorithms.

Machine learning is unlikely to aid autism diagnosis any time soon. There is wide variability in how autism shows up in boys and girls, how the condition is diagnosed, how neuroimaging is performed, and in the machine-learning algorithms used to draw conclusions from data.

To improve the accuracy of machine learning algorithms, Bisdas says, researchers should first standardize imaging methods.

“It doesn’t make sense to wait for more imaging data if we don’t standardize its collection,” Bisdas says. “Yes, we need more data, but we need more quality data.”

The results appeared in Neuroradiology in August.

Early-onset dementia and autism 

About 4 percent of adults with autism were diagnosed with early-onset dementia between 2008 and 2012, compared with less than 1 percent of non-autistic adults, according to a new study. The prevalence is more than 5 percent amongst people with both autism and intellectual disability.

The data came from Medicaid Analytic eXtract and included more than 1.2 million adults who received Medicaid benefits between the ages of 30 and 64. More than 12,000 people in the dataset have autism, 511 of whom were diagnosed with dementia before the age of 65. Among those with autism, the prevalence of early-onset dementia was higher for Black than for white people; it was also higher for those living in rural areas compared with city-dwellers.

The findings appeared in Autism Research in August.

Spectrum story spotlight: Prenatal exposure to antipsychotics does not increase autism odds

Children born to women who take antipsychotic medications during pregnancy, such as aripiprazole or risperidone, do not have elevated odds of having autism or attention deficit hyperactivity disorder, nor are they more likely to be born preterm or underweight, according to a study published in JAMA Internal Medicine in August.

Prescribing antipsychotics during pregnancy can help prevent potentially dangerous psychotic episodes and ensure that an expectant mother can take care of herself, says Mady Hornig, associate professor of epidemiology at Columbia University, who was not involved in the study. “We certainly don’t want to be cavalier about the use of any medication during pregnancy, but one also wants to balance out the implications of not treating.”

Any apparent effects of antipsychotics on a developing fetus are likely due to the condition that is being treated, rather than the treatment itself, the study shows. That’s because doctors prescribe medications for a specific reason, which can lead to additional differences between women who do and don’t take medications, and can skew study results. This explains why women who were medicated during pregnancy appear to have an increased hazard ratio for giving birth to children with autism, as shown in the chart above.

The findings appeared in JAMA Internal Medicine in August.

Spectrum index:

27: The number of co-occurring conditions, such as epilepsy and intellectual disability, that affect significantly more women than men with autism. The results appeared in the Journal of the American Medical Informatics Association in August.

336.6 percent: The increase in autistic adults who received supplementary security income awards, a U.S. cash assistance program, in 2019 compared with 2005. The greatest increases were in New Jersey, Delaware and Connecticut, according to a study published in the Journal of Autism and Developmental Disorders in August.

1.35: The increased odds that an autistic person’s cousin will have depression, compared with someone not related to an autistic person. The result, published in the Journal of Child Psychology and Psychiatry in August, drew on data from nearly 2.4 million people in Sweden. Many other conditions, including anxiety, eating and psychotic disorders, were also more common among relatives of people diagnosed with autism.

Dataset spotlight: A new longitudinal dataset of the developing mouse brain, created using resting-state functional connectivity data on the cortex, tracks postnatal development from a batch of animals across time. A preprint describing the data appeared on bioRxiv in April.

Cite this article: https://doi.org/10.53053/QGXY6857

The post By the Numbers: Machine learning, dementia link, antipsychotics while pregnant appeared first on Spectrum | Autism Research News.

About 1 in 15 men carries gene-damaging mutations — some with ties to autism or congenital heart disease — only in his sperm, a small study suggests.

An advanced DNA-sequencing technique detected the ‘mosaic’ mutations among 25 men in the general population. Mosaic mutations arise after conception and thus occur in only a fraction of the body’s cells.

“When you’re looking at sperm mosaicism, you’re right at the heart of what’s going to happen in the next generation,” says lead investigator Joseph Gleeson, professor of neurosciences and pediatrics at the University of California, San Diego.

Men accumulate mutations in their sperm as they age. Some researchers say these mutations explain why a man’s chances of fathering an autistic child double between the ages of 30 and 50, whereas others suggest these mutations account for less than 10 percent of that rising likelihood. But the prevalence of the mutations detected in the new study remained constant over a 12-month period, suggesting that these genetic alterations arose when the men were embryos. The advanced sequencing method the team used can also calculate the likelihood that a child will inherit the mutations — odds that similarly remain stable over time.

“What they show is that mosaicism is a small but significant contributor” to autism and congenital heart disease, says Anne Goriely, associate professor of human genetics at the University of Oxford in the United Kingdom, who was not involved in the study. “And that analysis of sperm allows you to tackle this.”

Mutation mystery:

Because many of the genetic mutations that contribute to a person’s autism cannot be detected in their parents’ blood, they are thought to arise spontaneously, or ‘de novo,’ around the time of conception or in the parents’ egg or sperm. In line with this idea, Gleeson and other researchers have previously detected these de novo mutations in the sperm of fathers with autistic children.

When the team presented their findings, though, “we always felt like we got the same questions,” says study investigator Martin Breuss, assistant professor of pediatrics-clinical genetics and metabolism at the University of Colorado in Denver. Because men constantly produce new sperm, would a mutation identified in any given sperm sample still be there in subsequent samples? And would these mutations become more prevalent with age?

To address those questions, the team took blood and sperm samples from 25 men up to three times over the course of one year. The men ranged from 18 to 70 years old. The researchers sequenced the entire genome of each sample at least 300 times — about 10 times more than traditional methods do. This deep sequencing enabled them to confidently distinguish mosaic mutations from sequencing errors.

“Without the advancing of the sequencing technology, it’s almost impossible,” to find mosaic mutations, says study investigator Xiaoxu Yang, a postdoctoral researcher in Gleeson’s lab.

The men carried an average of 33 mutations in their sperm, two-thirds of which are not detectable their blood, the team found. The results appeared in Cell in August.

Deep sequencing:

The fraction of sperm containing these mutations remained the same for each man over time, and the sperm-only mutations were no more common among older men than younger ones. Taken together, this means that the mutations likely occurred during embryogenesis, the researchers say.

“By measuring the percent of cells with [a specific, potentially damaging] mutation, we can actually make a prediction about the chance of having a child with the condition,” says Gleeson. If 5 percent of a man’s sperm contain a mutation today, for example, that gives him a 5 percent chance of passing that mutation on to his children today, tomorrow and 10 years from now.

Of the mutations detected only in sperm, an average of 1.6 per sample occur in the coding regions of genes, and 0.3 are predicted to affect a gene’s function, the researchers found.

Such loss-of-function mutations in one copy of a gene appear in the sperm of about 7 out of 100 men, the team estimates. These mutations could account for about 15 percent of cases of autism, congenital heart disease and severe pediatric conditions, they say.

Of note, the study focused only on ‘clonal’ mutations and not the more prevalent but less detectable ‘nonclonal’ ones, which occur in only a single sperm.

“To have a full picture of disease risk for a particular individual’s offspring, you also need to look at the nonclonal variants as well,” says Maria Chahrour, assistant professor of genetics and neuroscience at the University of Texas Southwestern in Dallas, who was not involved in the study.

Gleeson says he and his colleagues hope to explore these variants in the future with larger sample sizes, he says. “There’s a whole other world we haven’t even explored yet, which are these nonclonal mutations.”

Cite this article: https://doi.org/10.53053/NWPS6737

The post Mutations linked to autism may be detectable in men’s sperm appeared first on Spectrum | Autism Research News.

The X chromosome holds stronger-than-expected genetic sway over the structure of several brain regions, a new study finds. The X-linked genes that may underlie this oversized influence have ties to autism and intellectual disability.

“There were already hints that the X chromosome was likely to be conspicuous, with how involved it is with the brain,” says lead investigator Armin Raznahan, chief of the section on developmental neurogenomics at the U.S. National Institute of Mental Health. Many X chromosome genes — including those at the root of several autism-related conditions, such as fragile X syndrome and Rett syndrome — are expressed in the brain, for example.

But the new findings suggest that the X chromosome, despite containing only 5 percent of the human genome, has a privileged role in shaping the brain — one that may be particularly relevant to developmental conditions. What’s more, this influence may be stronger in men than in women, the study shows.

“What they’re showing is X is fundamentally different,” says David Glahn, professor of psychology at Harvard University, who was not involved in the new study. “It’s off the scale.”

Research over the past decade has linked genetic variation to shifts in brain features, such as overall size or patterns of connectivity between regions, Glahn says. But “the X chromosome and the Y chromosome are fundamentally understudied,” because including them requires extra analytical legwork, he says.

That oversight may soon wane, thanks to powerful datasets that compile gene sequencing and brain imaging data from tens of thousands of people. The new work is the latest in a series of studies that tap the UK Biobank, which houses genetic and imaging data from almost 40,000 people.

“The ability to look into [the] X chromosome and the influence on brain structure has really not been possible until these huge datasets have become recently available,” says Neda Jahanshad, associate professor of neurology at the University of Southern California in Los Angeles, who was not involved in the study. “This is a really important initial investigation into that.”

X files:

Raznahan and his colleagues analyzed genetic data and magnetic resonance imaging scans from 32,256 adults, roughly half of whom are women, from the general population.

From the brain scans, the researchers determined the thickness, volume and surface area of 358 regions of each participant’s cortex. They searched for links between these structural features and tweaks in the participants’ genetic code and then calculated the proportion of variation in the cortical features tied to that on the X chromosome. Raznahan and his team reported their results in July in Nature Neuroscience.

The X chromosome exerts a larger influence on the structure of several brain regions, including the prefrontal cortex, sensorimotor cortex and temporoparietal junction, than would be expected for its genomic size, the researchers found. And this pattern was more apparent for surface area than for a brain region’s thickness or volume. In fact, genetic variation on the X chromosome explains more than 20 percent of the variation in several regions’ surface areas, the study found.

The chromosome’s influence on the temporoparietal junction is particularly intriguing when it comes to autism, Glahn says. The region’s activity and folding is linked to theory of mind, or the ability to intuit the feelings and thoughts of others. Some autistic people find this skill challenging.

Networks involving attention, decision-making and sensory and motor function overlap significantly with the brain areas most influenced by X chromosome variation, the researchers also found, suggesting that the X chromosome supports adaptive behavior, Raznahan says.

“The structural organization certainly gives an initial insight,” Jahanshad says. But a key next step is to correlate genetic variation on the X chromosome with patterns in functional imaging data and actual behavioral traits. (Raznahan says he plans to do just this in follow-up studies.)

Sex effects:

A separate analysis yielded 20 X-linked genes that are associated with the surface area of the brain regions that show strong X chromosome influences overall. Several of these genes are implicated in intellectual disability, hydrocephalus and autism.

The work complements another UK Biobank study, published in April in the same journal, in which a separate team zeroed in on specific X chromosome genes tied to brain features, such as the integrity of nerve bundles in the brain.

The X chromosome’s sway over brain anatomy was more than twice as large for men than for women, Raznahan’s team also showed. The degree of this heritability difference between men and women correlated with the degree of sex differences in cortical surface area, which tends to be larger in men.

If the X chromosome plays a more significant role in determining some aspects of brain structure in men than in women, as the findings suggest, it may be compensation for men having only one X, whereas women have two.

The results add yet another string of evidence for the oft-contested idea that there are sex differences in the brain. But it’s not clear how the X chromosome might affect these differences or how they tie to actual behavior, Glahn says. “What’s really interesting about this is just asking those sex difference questions.”

Overall, the new work serves as a call to action for researchers to include the X chromosome as they probe the genetic patterning of the brain, Raznahan says. “We’d be delighted if this work in any way contributed to encouraging people to study the X chromosome more.”

The post X chromosome exerts extra influence on brain development appeared first on Spectrum | Autism Research News.

My lifelong fascination with science centers on its potential to improve our lives in practical and meaningful ways. I began my career as a clinical and research psychologist focused on autism more than a generation ago, when autism research was rapidly expanding. It seemed inevitable that basic science investigating autism’s characteristics and causes would begin to yield insights that we could translate into increasingly effective interventions. I expected to witness a gradual shift from basic science toward studies of interventions that systematically targeted specific skills, behaviors and populations.

I also expected that such translational research would begin to move beyond academic centers and into the community, where investigators could demonstrate how to scale up effective practices to reach everyone living with autism, including those whose behaviors and levels of co-occurring intellectual disability put them at risk for placement outside the home. And as my own daughter with this condition approached adulthood, I hoped to see more research demonstrating programs and practices that promote a better quality of life for adults with autism.

Unfortunately, these kinds of shifts did not occur. The preponderance of autism research has remained centered on basic rather than applied science, according to my own research and studies by others. I have spent much of the past decade trying to understand why the arc of research hasn’t bent further toward impact.

Autism research arc:

To delve into this question, I examined papers published in the Journal of Autism and Developmental Disorders (JADD), focusing on the years 1979, 1989, 1999, 2009 and 2019. My analysis appeared in a special May issue of the journal marking four decades since ‘autism’ debuted as a distinct diagnosis in the Diagnostic Statistical Manual of Mental Disorders, the diagnostic manual used in the United States. JADD is the only autism-focused journal spanning that history.

My review of all content from the five selected years yielded 616 articles describing original empirical research (as opposed to review articles, case studies, letters and commentaries). Ninety percent were published during the last two years I examined, confirming the explosion in research that many of us have witnessed. In fact, more articles were published in 2019 than during the four previous time points combined, likely reflecting the increase in U.S. research funds after the Combating Autism Act was passed in 2006.

I classified each of the 616 studies as basic or applied research. Basic research, by my definition, explored the characteristics, associated features, general trajectories and possible causes of autism. Applied research included studies that directly tested assessment or intervention practices with clinical populations and studies addressing factors that might influence these practices, such as disparities in access to services.

I found no evidence of a shift toward applied research over time. The proportion of publications focusing on basic research remained between 58 and 60 percent, except in 1989 when it spiked to 80 percent. Although some types of applied research — such as surveys of treatment practices and studies of web-based tools and supports — increased over the years, research on interventions decreased from between 24 and 31 percent in the first two time periods to just 12 percent in the last two time periods. Moreover, most intervention research continues to occur in specialized university or hospital settings. Only 6 percent was conducted in community settings, a proportion that did not grow during the study period.

One of the more disappointing trends is the lack of research on interventions that might help individuals with the greatest degree of disability. The proportion of treatment studies that included children with a severe form of autism decreased from 1991 to 2013, according to a 2018 review of the literature. This suggests that the arc of research bends away from those who may have the most to gain.

Research road map:

Despite the lack of movement toward applied research that touches communities, there is a partial road map for this trajectory. Two popular tools for autism screening and diagnosis — the Modified Checklist for Autism in Toddlers and the Autism Diagnostic Observation Schedule — grew out of basic research more than 30 years ago. They have since been widely adopted in applied research and may contribute to the early identification of autism that so many say is critical to improving outcomes. The missing piece is determining just how much these instruments have affected community practice, such as access to early intervention.

There is an obvious reason why applied research in general and community-based intervention research in particular remains stunted. Such studies are simply harder and costlier to do. The latter requires that researchers build partnerships with community agencies. This takes time, and it slows the pace of publications that new researchers need to launch a career in an increasingly competitive world.

Additional investigations will be needed to better understand trends in autism research. My study simply counted the number of studies in one scientific journal. Would the findings be the same for other journals focused on autism? Are there other ways to characterize the relative emphasis of basic versus applied research in either research publications or funding? And, of course, it is possible that in another decade or so we will see the arc begin to bend. We may simply need more time for basic research to pave the way not merely for more basic research but for better education programs, treatments and outcomes.

Peter Doehring is an independent autism researcher and consultant based in Chadds Ford, Pennsylvania.

Cite this article: https://doi.org/10.53053/KKFR6463

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The scientists in Ethan Scott’s lab at the Queensland Brain Institute in Brisbane, Australia, hail from a dozen different countries, including North Macedonia, Tahiti and the Seychelles Islands. Their specialties are equally diverse, spanning the fields of genetics, mathematics, computer science and optical physics. Together, the team spins what Scott calls a “web of expertise” for understanding sensory issues of the type that autistic people often have.

“We’ve been really lucky in the people we have attracted,” says Scott, associate professor of neuroscience at the University of Queensland. Scott is a transplant himself: He grew up in Newark, Delaware.

The focus of Scott’s work is the zebrafish, a transparent tropical fish native to South Asia, whose brain can be observed in action to a degree not possible with any other vertebrate — with the right tools, that is. His team uses zebrafish autism models to investigate how sensory brain circuits may differ in people with autism. In pursuit of the zebrafish’s neural secrets, Scott is willing to foray into unfamiliar disciplines, such as physics and mathematics. “I get really excited about getting novel types of results, and often this requires bringing new approaches into play,” he says.

Scott says he is also committed to social diversity and equity, particularly when it comes to gender, and has worked with his university to develop more equitable hiring practices. He told Spectrum about his feminist mother, streaming baseball games in the winter and a trick that makes stationary zebrafish “think” they are spinning.

Spectrum: What big question drives your research?

Ethan Scott: It’s this: How do animals sense and respond to the world around them?

Now comes the fun part, where the “big question” splits into a bunch of smaller ones: How is information from different senses integrated? How does processing change in response to repeated stimuli? How does recent experience, or context, impact sensory processing? How are sensory networks altered in psychiatric disorders?

S: How are you answering those questions?

ES: One of the challenges of studying sensory networks has always been that brain-wide functional imaging — functional magnetic resonance imaging, for instance — doesn’t resolve individual neurons, and targeted approaches like electrophysiology can’t see the whole brain. Neither approach reveals sensory networks for what they are — large, diverse and distributed populations of neurons.

Zebrafish are the only vertebrate model in which whole-brain imaging of individual cells is possible. Their larvae are also small, transparent and develop in the open. We have a system where we can see the entire brain functioning at cellular resolution — tens of thousands of neurons at once.

S: What is that system?

We detect the calcium that is naturally released within active neurons. We do this by expressing fluorescent calcium-binding proteins in zebrafish neurons across the whole brain. The higher the calcium levels in a cell, the more fluorescence we will see, and that’s how we know which neurons are active at any particular time. We detect the fluorescence signal using something called a light-sheet microscope.

Our light-sheet microscopes, which we custom build, provide a thin sheet of tightly focused light that illuminates one plane in the animal’s brain at a time. If we move the light sheet and the focal plane very quickly, we can collect images at different depths in a short period of time. That reveals activity across tens of thousands of neurons, sampled twice a second, across the whole brain.

We track this activity as zebrafish detect and respond to sensory stimuli. Using a variety of mathematical approaches, we then model how information flows through the system, and how this information flow changes in genetic models of autism.

Instrumental work: Ethan Scott makes adjustments to one of his lab’s custom light-sheet microscopes.

S: This work requires a lot of different kinds of specialized expertise. How did you gather that?

ES: I’ve been very lucky to have great people in my lab who have brought expertise from other fields. For example, Itia Favre-Bulle, a postdoctoral researcher in my lab, is an optical physicist by training. She built our light-sheet microscopes and sculpted light into custom holograms to perform optogenetics — a way to artificially stimulate particular sets of neurons with light — inside the intact zebrafish brain. For her, these were just parts of the physics tool kit, but for us neuroscientists, it was wizardry.

Her coolest trick was to use ‘optical tweezers’  — focused light beams that apply force to the objects they target — on the ear stones of zebrafish larvae to trick the larvae into thinking that they are spinning even when they are stationary. Because the larvae were still, we could put them under our light-sheet microscope and describe the brain-wide vestibular network, which would have been impossible if we had actually been spinning the animal. It was a creative and technical tour de force on her part, and it was a lot of fun to be part of.

S: How does your work help people with autism?

ES: Many people on the spectrum have atypical sensory processing — auditory hypersensitivity, for example, or issues combining information from two senses. We study sensory networks and the ways that the brains of animal models of autism process sensory stimuli differently from control animals.

In 2020, for example, we reported changes in auditory brain networks that seem to underlie auditory hypersensitivity in a zebrafish model of fragile X syndrome. This hints at a potential mechanism for such hypersensitivity in fragile X and autism.

S: How has the pandemic affected your work?

ES: It’s changed my approach to managing a lab. I always try to keep an eye on my people’s well-being, but during COVID-19, it’s been my whole job. I have a lot of international lab members who have been separated from their partners or families, and others who are supposed to join us but are stuck overseas. Our sense of community and mutual support has been essential to staying afloat. It’s reinforced my view that a lab has to be a positive community first and a scientific team after that.

S: You are active around the issues of equity and diversity. What do you do, and why?

ES: I’ve worked across my university and with the Australasian Neuroscience Society on equity and diversity issues, especially focusing on gender equity. My particular niche has been in job searches, interviews and hiring, which are rife with practices designed by and for white guys.

My mother is a retired professor and a powerful feminist, and I think I just grew up expecting women to be successful and in positions of leadership. Growing up in this setting was good for my image of women but may have left me naive to how deep and pervasive society’s inequities are. Starting my own lab and mentoring women — and working alongside female colleagues who have struggled with institutional biases — has made it clear to me how far we have to go, both institutionally and culturally. Raising two boys has also been eye-opening in terms of the gendered pressures and expectations that society applies to kids.

S: You grew up in the United States, so how did you end up in Australia?

ES: My postdoc was in San Francisco, California, and my partner’s was in Santa Barbara, California, and this arrangement got pretty old after a couple of years. She got a great offer as a lab head here, and they came up with a lab head position for me, too. With two tenure-track offers from a good university in a nice place, the Pacific Ocean seemed like a pretty small obstacle.

S: What does a typical day look like for you?

ES: Generally, I walk my boys, ages 8 and 11, to school and ride my bike to work from there. When I’m not teaching or in meetings, I am either hiding in my office writing grants or manuscripts, or I’m poking around the lab talking to the team. Like a lot of scientists, I live for the moment when new data have dropped and we can make our first tentative interpretations, so I’m poring through fresh data with my lab members whenever possible.

About once a week, I work from home, and that’s good if I want to focus on something without interruption. My dog loves the company, too. The evening brings cooking, dinner with the family and bedtime stories for the boys.

S: What do you listen to while you work?

ES: If I’m doing anything that requires focus, I can’t handle music with lyrics or a big dynamic range, so maybe just some early choral music or solo piano, or more often, just quiet. If work is light and the timing is right, I’ll stream the radio broadcast of a San Francisco Giants game. They’re on in the middle of the day during the winter in Australia, which is pretty weird, but I’ve gotten used to it. 

S: What do you do for fun?

ES: Fun usually means finding ways to unwind as a family. We’ve taken up archery, and we go once or twice a week together to shoot. I’ve also enjoyed woodworking as a hobby ever since I took night classes in woodworking at San Francisco City College as a postdoc. The boys are reaching an age where I can bring them in on furniture-making projects, and that’s great quality time.

Beyond that, we get outside whenever we can. We love to take the whole crew walking on the beach or hiking in the rainforest. We’re three-season campers, but not in the way that North Americans would expect; it’s beautiful in the winter here, but too hot in the summer.

S: How many unread emails are in your inbox right now?

ES: Zero! Unread emails make me anxious.

Quality time: Scott collaborates with his son on a woodworking project.

Cite this article: https://doi.org/10.53053/WYTQ6197

The post Beyond the Bench: A conversation with Ethan Scott appeared first on Spectrum | Autism Research News.

Hello, and welcome to this week’s Community Newsletter! I’m your host, Chelsey B. Coombs, Spectrum’s engagement editor.

A flurry of tweets this week touted a new Autism study from researchers at McGill University in Montreal, Canada.

How can we create inclusive methods to capture experiences of autistic youth w/ diverse cognitive & language abilities?@ValrieCourchesn,@RackebT et al explored new ways to amplify the voices of autistic youth across the spectrum

???? by @ValrieCourchesnhttps://t.co/a18KNJgIpe

— Autism Journal (@journalautism) September 6, 2021

The researchers piloted a new protocol, called “Autism Voices,” for collecting the first-person perspectives of young autistic people. The method involves surveying parents or caregivers to develop a semi-structured interview tailored to an autistic person’s communication preferences and needs. The researchers used picture cards, for example, and participants could answer by writing, texting with emojis, drawing, pointing, speaking or using augmentative or alternative communication devices.

Autistic participants had the most positive experiences with the most flexible interviewers, who might ask an unanswered question in a different way before moving to the next one. And participants who were minimally verbal or intellectually disabled were able to offer their own perspectives so long as their needs were taken into account, the study found.

“This methodology and approach to engagement will ultimately lead to the empowerment of the autistic community and will promote their self-determination by including them as active stakeholders in research that affects them,” the researchers wrote.

The paper highlights that it's feasible to include youth across the spectrum in participatory research. While minimally verbal or intellectually disabled participants tended to communicate in unconventional ways, they still communicated, were engaged and had things to say!

— Autism Journal (@journalautism) September 6, 2021

Michelle Dawson, an autism researcher at Hôpital Rivière-des-Prairies in Montreal, Canada, quoted the study directly.

A new protocol ("Autism Voices") for interviewing autistics aged 11-18, pilot study, free https://t.co/LtFrsxTreL "Our communication codes and processes allowed for an in-depth analysis of what otherwise could have been considered unsuccessful interviews"

— Michelle Dawson (@autismcrisis) September 4, 2021

The Olga Tennison Autism Research Centre at La Trobe University in Melbourne, Australia, tweeted that it is important such work continues.

So important that work continues on different ways that the voices of autistic people can be heard, given their communication differences https://t.co/PxEOGYrqHd

— Olga Tennison Autism Research Centre (OTARC) (@OlgaTennison) September 6, 2021

Elsewhere on Twitter, researchers raved about a new resource published in Cell that combines chromatin and transcriptional profiles in the developing human cerebral cortex.

Now online! Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution https://t.co/J2yiThzFDm

— Cell (@CellCellPress) August 13, 2021

PlumX Metrics shows the paper’s social media splash.

Investigator Sergiu P. Pasca, associate professor of psychiatry and behavioral sciences at Stanford University in California, thanked his collaborators on the research, which he described as an “effort to understand the logic of lineage progression & map #autism mutations.”

Our work on human cortical development is in @cell today. Effort to understand the logic of lineage progression & map #autism mutations Collab work with @WJGreenleaf
Led by????: Alex @atrev_bio & Fabian (@EpigenomeI) & Jimena (@jimena_andersen) & Laksshman https://t.co/kZ3IxAha2V pic.twitter.com/NXb4YAvpWD

— Sergiu P. Pasca (@PascaStanford) August 14, 2021

Ashley Watson, senior scientist at STEMCELL Technologies, called it an “incredible resource.”

Incredible resource. I'm particularly fascinated by the analysis method used to prioritize ASD mutations, and the finding that CTCF motifs were frequently disrupted in cases v. controls. Another clue that chromatin architecture is critical component of ASD pathogenesis? https://t.co/mwia62dBIu

— Ashley Watson (@lashleywatson) August 20, 2021

And Yang Luo, instructor of medicine at Harvard University, commented on the “many cool methods to dive into.”

great work from @PascaStanford& @WJGreenleaf lab.Paired chromatin and transcriptional profiling in developing (human) brain.Many cool methods to dive into.Resources for predicting cell-type specific activity at single nucleotide res.https://t.co/Gj3EHDHZj1 https://t.co/JcQ87QtNRQ pic.twitter.com/WioRnNigaU

— Yang Luo (@yluo86) August 16, 2021

If you missed our 31 August webinar with Laurent Mottron, professor of psychiatry at the University of Montreal in Canada, you can now watch it on our site.

And don’t forget to register for our 28 September webinar, featuring Jeremy Veenstra-VanderWeele, professor of psychiatry at Columbia University, who will speak about goals for developing new drugs for autism — and the barriers researchers may encounter.

That’s it for this week’s Spectrum Community Newsletter! If you have any suggestions for interesting social posts you saw in the autism research sphere, feel free to send an email to me at chelsey@spectrumnews.org. See you next week!

Cite this article: https://doi.org/10.53053/DUZE8641

The post Community Newsletter: “Autism Voices” and the developing cortex appeared first on Spectrum | Autism Research News.

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Brain scans from 16 mouse models of autism reveal at least four distinct patterns of brain activity, a new study suggests. The findings lend fresh support to the popular idea that autism is associated with a range of brain ‘signatures.’

Telltale neural signatures of autism have long proved elusive, with functional magnetic resonance imaging (fMRI) and other brain scanning technologies shouldering the blame for scattered and inconsistent results.

“One big question is whether there’s a single signature of dysfunction in the brain of people with autism. And many people consider that to be, like, something that there must be,” says study investigator Alessandro Gozzi, senior researcher at the Istituto Italiano di Tecnologia in Rovereto, Italy. “If we’ve not found it yet, the blame must be on the method: fMRI.” The method gauges small changes in blood flow and oxygenation as an indirect measure of brain activity.

For the new study, published in Molecular Psychiatry in August, Gozzi and his colleagues used fMRI to study brain connectivity patterns — or which brain regions ‘talk’ to each other, and to what degree. Brain regions are considered to be in communication if they have synchronous oscillations in blood flow.

To tackle the question of reproducibility in fMRI, the researchers conducted their analysis in mice, anesthetizing the animals and fixing their heads in place to prevent any motion that could perturb brain signals. “We moved to a model organism where we can control, in exquisite detail, many of the factors that are considered to be at the basis of this variability, this unreliability in imaging,” Gozzi says.

The 16 mouse models fall into four groups based on brain activity patterns, the analysis found. For example, one group shows increased connectivity between areas in the prefrontal cortex and amygdala, social and emotional regions of the brain, respectively; another group has increased connectivity between the hippocampus and ventral orbital cortex, regions involved in memory and higher cognitive functions.

“I think we know, from a behavioral point of view, that autism is very heterogeneous,” says Kaustubh Supekar, clinical assistant professor of psychiatry and behavioral sciences at Stanford University in California, who was not involved in the study. “Expecting that we were going to find a common signature for such a heterogeneous condition was sort of a pipe dream.”

Clustered connections:

Gozzi and his colleagues, at locations in Italy and Switzerland, imaged 350 animals, including controls and roughly the same number from each of the 16 autism mouse models: 13 models with autism-linked mutations, including in the genes SHANK3, FMR1 or MECP2; mice deficient in microglia, immune cells that sculpt neuronal connections; mice exposed prenatally to the immune signaling molecule IL-6; and an inbred strain called BTBR.

A machine-learning model trained on the fMRI data clustered those results into four groups. Mice with mutations in the genes CHD8 or SYN2, those with deletions in chromosomal region 16p11.2, and the BTBR and IL6 models all have reduced neuronal signaling between the cortex, striatum and inferior colliculus, but increased signals between the ventral orbital cortex and hippocampus.

By contrast, mice with mutations in SHANK3, CNTNAP2 and SGSH, have reduced activity between the hippocampus and insula, and a moderate increase between the nucleus accumbens and hypothalamus.

The other mouse models, such as those with mutations in CDKL5 or MECP2, or animals with missing microglia, clustered into two additional groups with entirely different neuronal activity patterns.

Clinical start:

Though it focused on mice, the new study could have clinical implications, researchers say.

“This clustering of different subgroups of animal models really provides a first step in trying to understand what could be expected in humans,” says Itamar Kahn, associate professor of neuroscience at Columbia University, who was not involved in the study.

People and mice harboring a 16p11.2 deletion, for example, have similar changes in brain connectivity, Gozzi’s group previously showed.

But Gozzi’s use of anesthesia could be problematic, says Vinod Menon, professor of psychiatry and behavioral sciences at Stanford University, who was not involved in the study.

“The anesthetized brain is very different from an awake, behaving brain,” he says. “There’s no question this study will have a big impact, and I think it’s an important step, but it will be interesting to see what happens in the case of non-anesthetized mice as well.”

For future studies, Gozzi says he plans to triple the number of autism animal models scanned, which may yield additional brain connectivity ‘clusters.’

“We want to scan at least 50 [mouse models] to begin to talk about how different mutations can be grouped based on connectivity,” he says.

Scanning mice with one mutation at a time, though, may not accurately reflect autism’s complexity. Many autistic people harbor numerous mutations that contribute to their condition.

“We know these genes don’t work in isolation,” Supekar says. “So then this becomes an exponentially complex thing, where you need to create models with a lot of genes knocked out at once.”

Cite this article: https://doi.org/10.53053/JUPD6575

The post Autism mouse models cluster by brain activity pattern appeared first on Spectrum | Autism Research News.

A new gene delivery system taps a protein found in people to encapsulate messenger RNA (mRNA), the intermediary between genes and proteins, and transport it into cells. The technique may help researchers ferry gene therapies or the gene editor CRISPR into tissues throughout the body.

“We’ve been working on gene therapy and gene editing for a long time now, and the tools are getting to be pretty good,” says Feng Zhang, professor of neuroscience at the Massachusetts Institute of Technology, who led the work. Researchers have only been able to get CRISPR into cells in some parts of the body, however, limiting the diseases they can target.

Empty viral shells often deliver genes used in research and in therapies. But these viral vectors can trigger immune reactions, and they carry genes only up to a certain size, which makes sequences that encode large enzymes — such as Cas9, the main DNA-cutting protein CRISPR uses — difficult to transport.

Another delivery approach involves enveloping genes inside lipid nanoparticles, but targeting specific tissue in this way remains challenging. Often, nanoparticles accumulate in the liver.

The new method, called Selective Endogenous eNcapsidation for cellular Delivery, or SEND, harnesses a human protein that ordinarily carries mRNA within a protective capsule, similar to a virus. Because the protein is naturally found in people, it may trigger less of an immune response than viral vectors. It can also carry larger payloads and, unlike nanoparticles, can be tailored to target specific cells. The researchers described the method in August in Science.

Some proteins derived from retrotransposons — segments of DNA that copy and insert themselves throughout the genome — form virus-like protein shells, previous studies show. A signaling protein implicated in autism called ARC, for example, encloses its own mRNA and shuttles it between cells.

To find other virus-like proteins, Zhang and his colleagues searched the genomes of mice and people for capsule-forming sequences similar to those found in some viruses and retrotransposons. The team then expressed the most promising candidate genes — focusing on those present in both mice and people — in bacteria and cultured human cells.

Protein pod:

Seven of the proteins the team analyzed formed virus-like structures, the researchers reported. The bacteria and cultured cells secreted one candidate, called PEG10, at higher levels than the others. Further analyses revealed that PEG10 binds to its own mRNA, often attaching to regions on both ends of the sequence that are not translated into protein.

The team took advantage these binding sequences to reprogram PEG10 to carry a different mRNA cargo. They sandwiched a sequence encoding a protein called Cre between the two untranslated regions in PEG10 and introduced the flanked Cre sequence into a batch of human cells, along with mRNA encoding PEG10 and a fusogen, a protein on the surface of a virus-like capsule that enables the capsule to enter a cell. The researchers then harvested the virus-like proteins the cells secreted two days later.

When the team added the secreted capsules to a second batch of cells — this time, mouse stem cells engineered to express a green fluorescent protein in the presence of Cre — the cells glowed green, suggesting that the system had successfully delivered Cre mRNA.

Some fusogens target certain cell types and could be used to deliver genetic cargo to specific cells or tissues, the researchers say. In one experiment, for example, they delivered Cre mRNA to skin cells from mice, using virus-like particles equipped with a fusogen that targets these cells.

In another test, the team used the technique to deliver CRISPR into cultured cells from people. They encased mRNA encoding Cas9 and a sequence that guides the protein to cut a specific DNA target. DNA sequencing revealed that the system modified the targeted gene in about 40 percent of the cells.

SEND could help scientists develop therapies for autism, providing a way to safely and effectively deliver gene therapies or gene-editing treatments, the researchers say. It could also be used as a research tool to study the effects of specific genetic modifications.

“We really think that we can turn this into a very powerful toolbox,” Zhang says. The researchers plan to develop a repertoire of fusogens that target different cell types and test the system’s ability to carry a range of genetic cargoes.

Cite this article: https://doi.org/10.53053/BZTX8458

The post New method uses virus-like protein to package, deliver RNA appeared first on Spectrum | Autism Research News.

Over the past century, scientists have used a variety of animal models to advance their understanding of the developing brain and autism. Here’s a chronology of some of the landmark discoveries involving uncommon autism models.

1916

Notch up:

Biologist Thomas Hunt Morgan identifies a fruit fly gene called NOTCH that affects wing maturation and is part of a pathway later linked to nervous system development in people.

1920

Heart to heart:

Austrian scientist Otto Loewi observes parallel activity in two frog hearts suspended in saline, theorizing that a chemical messenger he dubs ‘vagusstoff’ traveled through the solution — the first identified neurotransmitter.

1962

Pluripotent possibilities:

English zoologist John Gurdon replaces the nucleus of a frog egg with a nucleus from an intestinal cell. The resulting embryo successfully develops into a tadpole, demonstrating that mature cells contain all the information needed to create any cell type and kicking off research in induced pluripotent stem cells.

1971

Fly time:

Biologist Seymour Benzer and a colleague demonstrate that mutations in a fruit fly gene dubbed PER disrupt the fly’s circadian rhythm, launching Drosophila melanogaster as a model for the study of how genes control behavior.

1986

Worm wiring:

Scientists publish the complete wiring diagram of the Caenorhabditis elegans nervous system, paving the way for the extensive use of roundworms in studies of nervous system development.

1990

Elegans experiment:

Studies show that C. elegans is capable of habituation, a simple form of learning that may be disrupted in autism.

2007

Mouse milestone:

Researchers debut a single-gene mouse model of autism: mice with a mutation in the gene NLGN3.

2010

Inching forward:

Scientists create one of the first invertebrate models of autism: a strain of C. elegans with a faulty version of the roundworm’s neuroligin gene NLG1.

2012

Fish tale:

A zebrafish study shows that multiple genes in the 16p11.2 chromosomal region, which may be deleted or duplicated in autism, play roles in brain development.

2015

Social space:

Researchers report that fruit flies in an enclosure tend to keep a reliable amount of space between them, an observation that can be used to investigate how mutations in autism-linked genes affect social behavior.

2015

Eight is enough:

The complete genome sequence of the California two-spot octopus (Octopus bimaculoides) is published, revealing striking similarities to people in genes involved in nervous system development and function.

2016

Sedated swimmers:

Zebrafish larvae lacking the autism-linked gene CNTNAP2 are hyperactive at night, but adding estrogen-like compounds to their tank calms the fish — demonstrating a use for the animals in screening potential autism treatments.

2018

Two to tango:

A study of gene expression in the developing fly eye reveals the importance of interactions between genes in the 16p11.2 region during neurodevelopment.

2018

Social circuits:

Researchers identify neurons in the forebrain of zebrafish that support their social interactions, suggesting that zebrafish can be used to probe social brain circuitry.

2019

Picking priorities:

An analysis of 20 autism-linked mutations in roundworms flags 10 autism candidate genes as worthy of further study, because of their impact on the worm.

2019

Gut feeling:

Scientists find that food moves through the gut slowly in zebrafish larvae with SHANK3 mutations, providing a clue to the roots of digestive problems associated with autism.

2019

Habit forming:

The behavior of fruit flies with mutations in autism-linked genes suggests that dozens of these mutations lead to impairments in habituation.

2019

Stranger danger:

Like their mouse counterparts, zebrafish lacking the autism-linked gene RELN show little interest in socializing with unfamiliar fish, supporting use of the fish as a model for social difficulties in autism.

2020

Roundworm rodeo:

A study of more than 27,000 roundworms with mutations in the worm versions of 98 autism-linked genes hints at the function of these genes; many of them affect habituation.

2020

Sound check:

Zebrafish larvae lacking FMR1, the gene altered in fragile X syndrome, are hypersensitive to sound, suggesting that zebrafish can be used to study sensory processing differences in autism.

2021

Show stopper:

Reducing the expression of the autism-linked gene FOXP1 in a particular brain region in songbirds impairs the birds’ ability to memorize songs they hear from their fathers, suggesting a specific role for this gene in language learning.

2021

Fly by night:

Fruit flies lacking a gene akin to the autism-linked genes CHD7 and CHD8 have fragmented sleep, a problem researchers corrected using an adapted form of  ‘sleep restriction,’ an insomnia treatment.

Cite this article: https://doi.org/10.53053/TIYT8223

The post Fish, frogs, flies and other fauna in scientific firsts appeared first on Spectrum | Autism Research News.

In the past two decades, some autism researchers have turned to simple animals, such as roundworms, fruit flies and zebrafish, for their investigations. Others have sought answers from experiments with frogs, birds and even octopuses. In this special report, we describe these discoveries and the impact that alternative animal models have had on autism research.

The post Special report: Unusual animal models of autism appeared first on Spectrum | Autism Research News.

The post What studying worms, flies and fish says about autism appeared first on Spectrum | Autism Research News.

Earlier this year, researchers reported striking similarities in the functions of 10 autism genes: They all affect brain size and boost the number of immature neurons in the brain. The work raised hopes of finding common biological paths to autism.

Most studies on gene function are done in mice, but this work involved a tiny tropical frog, Xenopus tropicalis, that is native to West Africa.

These frogs boast a slew of traits that make them useful for autism research. Each adult can lay thousands of eggs, which develop into tadpoles in only a week. After the fertilized egg divides, each daughter cell and all of its progeny stay on their respective side. This leads to a perfectly bisected animal that can host a mutation on just one side of its body. Researchers can then watch how those cells develop early on: The tadpole’s initial developmental stages occur outside of the mother’s body. What’s more, Xenopus can be induced to lay eggs any time, simply by exposing the frog to hormones.

The team edited each of 10 top autism genes in just one of the two original daughter cells in thousands of Xenopus eggs. As the tadpoles’ brains developed, their two sides developed differently: The inserted mutations led to an atypically large or small cerebrum and an unusually large number of immature neurons, all of it clearly visible to researchers. “This [tadpole] is just out on his own, swimming,” says study investigator Helen Willsey, a postdoctoral researcher in Matthew State’s lab at the University of California, San Francisco. “We can look into the brain while it’s alive and really watch all of brain development in a dish.”

Thanks to this transparency, research in frogs has led to foundational discoveries about the brain and nervous system, including that of the first neurotransmitter and of techniques to create human pluripotent stem cells. “Xenopus has been extraordinary in allowing us to watch the nervous system develop,” says Hazel Sive, dean of the College of Science at Northeastern University in Boston, Massachussetts.

Researchers continue to come up with clever ways to study autism and neurodevelopment in the amphibians. One research team used frogs to show that deletions in the chromosomal region 3q29, which are linked to autism, may accelerate the process of cell death, identifying a potential mechanism for the deletion’s effects. In an unpublished study, another team found that knocking out the autism-linked gene CHD7 in Xenopus laevis embryos disrupted the tadpoles’ head structure by decreasing expression of a collagen-producing gene. And in new work, Willsey’s group used frogs to show how certain genetic variants can contribute to both autism and congenital heart disease.

Willsey plans to work with Xenopus tropicalis to connect the various biological steps from autism genes to autism traits. “Going from genes to biology to circuits to behavior is a big leap,” Willsey says. “One nice thing about frogs is that in one system, you can do all of those things.”

Cite this article: https://doi.org/10.53053/WRUR5688

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The communication and language difficulties seen in people with autism are challenging to study in animals, for obvious reasons. But scientists have seen parallels between human speech and the songs of some birds. Young male zebra finches (Taeniopygia guttata) learn to sing by listening to and imitating adults, much as children learn to speak. In both songbirds and young children, this learning takes place during a ‘critical period’ early in development and involves analogous neural circuits. Because of these similarities, songbirds such as zebra finches have become important models for the study of language learning in autism.

Over the past several decades, scientists have developed detailed knowledge of song circuits in birds, says Todd Roberts, associate professor of neuroscience at the University of Texas Southwestern Medical Center in Dallas. This background “gives us a really good foundation” for evaluating the function of autism-linked genes that might play a role in language, he says: Scientists know just where to look in songbird brains for the effects of particular genes.

Many human brain regions governing speech show similar gene-expression profiles to those of song-related regions in birds. About a decade ago, researchers began to document how some autism-linked genes, such as CNTNAP2, are expressed at high levels in birdsong brain regions, suggesting that these genes play a role in the birds’ ability to sing. They have since tracked how the expression of certain autism-linked genes changes during the process of song learning. When young male zebra finches sing, the level of an autism-linked protein called reelin increases in a song-related region called Area X. So does the amount of the activated form of a protein called DAB1, which is also linked to autism. So these genes may be involved not just in singing in birds, but in learning to sing — and perhaps in language-learning in people, too.

In the past five years, researchers have disrupted the expression of various autism-linked genes in zebra finch brains to evaluate the genes’ roles in song learning. They have found that turning down production of CNTNAP2 in key song-learning areas of young male zebra finch brains impairs the birds’ ability to learn songs from their fathers. They have suppressed expression of FOXP1 or FOXP2, autism-linked genes involved in language in people, in the birds’ basal ganglia and found that doing so also impedes song learning. And a study published earlier this year suggested that dampening production of FOXP1 in a song region called HVC prevents young birds from learning new songs, although they can still practice and perfect songs they already know, hinting at a role for this gene in a specific aspect of the song-learning process.

Birdsong is not a perfect analog of language. A zebra finch’s song is a single repeated sequence, simpler than the rich tapestry of human speech. “We can recombine these sounds to have many different meanings attached, whereas with the bird the meaning is really just: ‘Hey, I’d like to be your mate,’” says Caitlin Aamodt, a postdoctoral researcher working with Eric Courchesne and Nathan Lewis at the University of California, San Diego.

But the similarities are strong enough that songbirds could help researchers understand language difficulties in autism and provide clues to improving language learning in autistic individuals. The birds might even provide a platform for testing treatments designed to bolster language skills. “One of the ultimate goals would be to understand at what stages of development you need to intervene by, and how strong or long-lasting those interventions need to be,” Roberts says.

Cite this article: https://doi.org/10.53053/BCCO9981

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Usually, conversations justifying animal models of autism center on how similar a species is to humans. But Gül Dölen takes a different view. “What if we went for the animal that is least similar to humans?” says Dölen, associate professor of neuroscience at the Johns Hopkins University in Baltimore, Maryland. “You want to compare across maximally different animals who can solve the same kinds of problems.”

That principle led Dölen to octopuses, invertebrates with eight arms, three hearts and blue blood. The animals do have at least one thing in common with people, however: They are known for being exceptionally clever. “Octopuses are able to do some fairly complex cognitive tasks,” she says, solving puzzles to access food, even outwitting their keepers to escape from aquariums. “And yet their brains look nothing like ours.”

Octopuses do not have a cerebral cortex or any of the brain structures that have been implicated in social cognition in humans. But at a molecular level, the octopus nervous system has a lot in common with ours. Dölen has found evidence that that the signaling molecules that underpin social behavior in people perform a similar function in octopuses.

This evidence came from an unorthodox experiment: Dölen and her team exposed the animals to 3,4-methylenedioxymethamphetamine (MDMA), the active ingredient in the drug ecstasy. MDMA interacts with receptors for the signaling molecule serotonin and thereby boosts sociability. It makes people feel especially close to and connected with others. If it had a similar effect in octopuses, the researchers reasoned, studying octopuses could yield insights into human social behavior and how it differs in autism. Scientists could also use the animals to test medications akin to MDMA that improve sociability.

Dölen and her colleagues put four California two-spot octopuses (Octopus bimaculoides) in water containing MDMA, allowing the animals to absorb the drug through their gills. Then they moved the animals, one at a time, to a tank where the animals had a choice of two chambers: One contained an object and the other housed another octopus (which was in an additional enclosure to prevent an altercation). After absorbing MDMA, the typically solitary, asocial creatures spent more time with the other octopus than the object. The reverse was true for controls, the researchers reported in 2018. The octopuses exposed to MDMA went so far as to press their bodies up against the enclosure containing the other octopus and wrap their arms around it as if in a hug.

Dölen thinks that studying octopuses could help scientists understand the molecular basis of theory of mind, the ability to infer what another creature is thinking. This skill may be altered in autism.

Some observations hint that octopuses have theory of mind, she argues. For example, the larger Pacific striped octopus hunts shrimp by stealthily reaching one of its arms around the shrimp’s body and tapping its back end. The shrimp then jumps forward, where the rest of the octopus is waiting to gobble it up. By contrast, the octopus pursues hermit crabs by pouncing from behind, suggesting that it knows shrimp can see things behind them — so it needs to be sneaky — but hermit crabs are blind to their backsides because of their shell.

Dölen plans to disrupt the octopus versions of autism genes and record the effects on the animals’ hunting behavior. This could suggest a role for these genes in social cognition in the context of a unique animal, which might in turn inspire new autism therapies, she says.

Cite this article: https://doi.org/10.53053/YMDC5342

The post Getting eight arms around autism appeared first on Spectrum | Autism Research News.

Muscat, Oman:

The Arabic sign-language interpreter stood at the front of the auditorium, his gestures perfectly in sync with the presenter’s passionate, French-accented speech.

The audience — more than 2,000 people assembled for the First Gulf Autism Conference in January 2020 — sat with rapt attention. “All these people were so quiet,” remembers Watfa Al-Mamari, a developmental pediatrician at Sultan Qaboos University in Oman and a conference organizer.

“You could hear a pin drop,” recalls Stephen Scherer, a geneticist at the University of Toronto in Canada.

The speaker was child psychiatrist Eric Fombonne, describing how he and others had, in the 1990s, debunked the erroneous idea that vaccines cause autism.

Fombonne pitched his talk at people with little scientific background. His listeners included politicians, policymakers, autistic people and their families, and the general public. Yet even the scientists and clinicians in the auditorium learned something new: Scherer took out his cell phone to snap photographs of Fombonne’s slides — something he says he had never done before — so that he could look up the references later.

In many ways, the talk was itself a snapshot of Fombonne’s four-decades-long career: a mix of rigorous science and public engagement, delivered with the kind of human warmth that makes him a respected colleague and sought-after clinician. Al-Mamari says she remembers seeing him later at the conference, surrounded by autistic people and their families.

Fombonne, 66, is best known for his studies of the patterns of autism distribution and prevalence. “Whenever I had any question about epidemiology, he was the one I would turn to,” says Uta Frith, professor emeritus of cognitive development at University College London in the United Kingdom.

But his contributions to the field are wide-ranging. He has published on topics from genetics to assessment tools, and his curriculum vitae, which includes academic positions in four countries, runs to 94 pages. Within the research community, colleagues say, Fombonne has been unusually good at forging international partnerships and unusually willing to stake out bold positions on the cause, prevalence and nature of autism.

Last year, for example, he waded into a debate about camouflaging, publishing an editorial arguing that the term — often used to describe how some autistic people change their behavior to appear neurotypical — has not been rigorously defined. The editorial prompted a lengthy response from scientists studying the phenomenon, but it wasn’t entirely unwelcome.

Fombonne “challenged the field of camouflaging research in a very constructive manner,” says William Mandy, a psychologist at University College London and one of the authors of the rebuttal. “[His] intervention is helping clarify areas of disagreement and misunderstanding, and is shaping the questions that future camouflaging research should address.”

Paris, France:

Fombonne was born in Paris and grew up in an affluent suburb. He was a strong student, interested in mathematics and science. He was also politically engaged and participated in student demonstrations in the late 1960s — activism he attributes to his parents, devout Catholics involved in social justice causes.

In medical school at the University of Paris, Fombonne chose to specialize in child psychiatry. At the time, there was “intellectual excitement about psychiatry because [of] the mystery of the mind,” he says, and child psychiatry seemed to hold the most therapeutic potential.

Another factor, too, helped guide Fombonne’s decision: Around the time he entered medical school, his older sister, Dominique, was diagnosed with schizophrenia. As a young medical student, he accompanied her to hospital emergency rooms on several occasions; after grappling with the illness for more than a decade, she died by suicide in 1986.

The experience left him keenly aware of the limitations of psychiatric care — and skeptical of theories that didn’t offer any practical help for patients and their families. “It certainly shaped my later sense that I needed to pursue research and to ask questions and challenge the views of the current establishment,” he says.

To that end, in the late 1980s Fombonne launched the first study of the prevalence of child psychiatric conditions in France while on staff at a psychiatric hospital in Paris. His work attracted the attention of a French association of families with autistic children, who inspired him to conduct the first epidemiological studies of autism in France. He soon became an advocate for improved autism care, speaking at conferences and lobbying the French government on the topic.

London, England:

Fombonne’s epidemiological studies earned him recognition as a rising star, and in 1993 he was recruited to join a group at the Institute of Psychiatry in London led by Michael Rutter, renowned as the ‘father of child psychiatry.’

There, Fombonne joined a community of like-minded clinician-researchers for the first time, he says. “There still are very, very exquisite relationships with some of my peers who I met during that period.”

His position in London also put him at the epicenter of child psychiatry when, in 1998, a bombshell hit: Now-discredited gasteroenterologist Andrew Wakefield published a paper in The Lancet alleging a link between the measles-mumps-rubella (MMR) vaccine and the onset of autism.

Fombonne was immediately skeptical. Within weeks of learning about the paper and before its publication, he had marshaled data from two existing datasets to refute Wakefield’s claims. And after the paper came out, Fombonne conducted multiple studies to test Wakefield’s hypotheses, always with the same result: Wakefield’s science was “completely bogus,” he says, vaccines were safe, and there was no connection between the MMR vaccine and autism.

Wakefield’s paper was later retracted — he had falsified his data — but Fombonne “was really almost prescient in understanding that this was going to have a big effect on families and on our field, and understanding the importance of bringing really rigorous science to evaluate whether that hypothesis was correct,” says Sally Ozonoff, a child psychiatrist at the MIND Institute at the University of California, Davis, who has known Fombonne for many years.

Fombonne gave talks on the vaccine controversy at medical conferences and at meetings of the Institute of Medicine in the United States. Despite death threats from anti-vaccine activists, he served as an expert witness in vaccine-injury trials. “I was not prepared to do all that in my career,” he says. “I remember I was so shy when I first gave talks in public, and then to be speaking in the court in Texas in English!”

However challenging, the work was fulfilling, he says, because he knew that widespread acceptance of an incorrect explanation of autism’s origin would harm people with autism and their families — and that there was a broader public health risk if people abandoned vaccines.

“It made me sense that the path that I had chosen for my career had a social impact,” he says.

Montreal, Canada:

Fombonne expanded his epidemiological work with another big move in 2001, becoming the Canada Research Chair in Child Psychiatry at McGill University in Montreal and head of the child psychiatry department at Montreal Children’s Hospital. From this post, he led a World Health Organization-sponsored review of how geographical and cultural variations impact autism prevalence estimates — work that has been cited more than 2,300 times.

Although Fombonne’s research documented an increase in autism prevalence worldwide, he is skeptical of the ‘autism epidemic’ framing that has dominated some discussions. Instead, he argues that other factors likely contribute to the uptick, such as a broader definition of autism and greater clinical recognition of it — another instance of his insistence on a careful accounting of the data before drawing flashy conclusions, Ozonoff says.

In Canada, Fombonne developed an autism research and clinical program, as well as a training program — the first of its kind in the country. Over the course of a decade, the program educated at least 150 early-career scientists, many of whom are now prominent autism researchers. “It had the reputation, even within the first few years, that you want to be seen there,” says Scherer, who taught in the program.

Al-Mamari participated in the training program in the mid-2000s and trained under Fombonne, as did Mayada Elsabbagh, a neuroscientist at McGill University who worked on the World Health Organization review and now directs a similar training program.

“Eric had a big influence in terms of my research trajectory and opened up opportunities that were quite nice and exciting, and ones that I still pursue today,” says Elsabbagh, who has been his frequent collaborator since.

Portland, Oregon:

Fombonne’s collaborations and epidemiological studies have taken him around the globe, to Mexico, China, Oman, Qatar, Kazakhstan, Morocco and Brazil.

“He is the ‘active ingredient’ in research teams now internationally,” Elsabbagh says. “I don’t know anybody who has done the same scale of international partnerships.”

And since 2011, he has been working to build another autism research program and clinical center at Oregon Health & Science University in Portland — a relocation prompted by his then-wife, who had lived in the city previously.

“I said, ‘Portland? Where is it, first? What is there for me?’” Fombonne recalls jokingly.

In each new country where he contributes to an epidemiological study or takes up an academic post, Fombonne aims not only to capture autism prevalence, but to build regional research and clinical capacities, and provide data that local policymakers need to develop autism services.

Fombonne builds partnerships not just on good science, but on good company, Elsabbagh adds. After a regional International Society for Autism Research meeting in Chile in 2019, for instance, political unrest forced them to road-trip out of the country, along with several other scientists. “In theory the circumstances were not very pleasant, but we actually had a really good time,” she says.

The coronavirus pandemic has put a temporary damper on Fombonne’s scientific travels, but he’s finding new ways to engage in social issues. Every weekend from March through June, he volunteered at a mass vaccination clinic at the Portland airport: “I put Pfizer, Moderna and J&J shots in thousands of arms,” he says. “Older arms at first, and later, younger and younger arms!”

Like his more usual work, it afforded him a mix of clinical practice and big-picture impact. “I enjoyed the experience,” he says. “Contacts with people were relatively brief, but I could see a cross-section of society and many interesting facets of human experience.”

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Cite this article: https://doi.org/10.53053/HXWI7309

The post Eric Fombonne: Crossing continents to expand autism science appeared first on Spectrum | Autism Research News.

Steve Warren, a giant in the field of human genetics, died in June at age 67. In the realm of autism research, he may be best known for having co-discovered the gene FMR1, mutations in which cause fragile X syndrome, a leading inherited cause of intellectual disability and autism.

Before the human genome was mapped, identifying a disease gene was a major undertaking into the unknown. In the case of FMR1, this painstaking process took nearly half a century.

Scientists first described fragile X syndrome in 1943 and observed its characteristic constriction near the end of the X chromosome’s long arm in 1969. By 1991, Steve and his collaborators had pinpointed the gene associated with this fragile site.

Steve’s lab had previously used a cumbersome technique called somatic cell hybridization, which involved fusing blood cells from a person with fragile X to rodent cells in culture dishes. They then treated the cells with reagents that induced translocations between the human and rodent chromosomes at the fragile X site. By cleverly tracking the genes lost on either side of the fragile X site in different cells, they had identified chromosomal region Xq27.3 as its location.

They then acquired DNA pieces that spanned the fragile X site and rearrangements in the hybrid cell lines, providing the precise address for the fragile X candidate gene, which they named FMR1. This crucial step also enabled the team to discover that repeats of the DNA ‘letters’ CGG in the gene cause fragile X syndrome. The size of this trinucleotide repeat expansion can increase over generations, and having more than 200 CGG repeats silences the FMR1 gene.

The same genetic mechanism has turned out to be relevant to multiple conditions, such as Huntington’s disease and several ataxias. And it explains the phenomenon of genetic anticipation: the observation that certain heritable conditions present more severely in later generations. Until the discovery of the repeat-expansion process, some textbooks dismissed the idea of genetic anticipation as a mere artifact of ascertainment bias — that is, that the symptoms of a heritable disease appear more obvious once one knows that the members of a particular family are at high risk for those symptoms.

For these and other discoveries, Steve received the William Allan Award from the American Society of Human Genetics, the organization’s highest honor. In 2001, he founded Emory University’s Department of Human Genetics, which he chaired until 2020. His scientific intellect and generosity are sorely missed.

Here we share our individual reflections about Steve:

Joseph Cubells: I first met Steve in 2003, when I had the privilege of traveling to Emory to present my work on the genetics regulating the activity of an enzyme called dopamine-beta-hydroxylase in human serum. After I met with Steve, and subsequently with Charlie Nemeroff, then the chair of psychiatry and behavioral sciences at Emory, Steve and Charlie decided to recruit me to Emory from Yale.

How many chairs of human genetics do you know who would recruit a psychiatrist to take a primary appointment in his or her department? Perhaps Steve liked the idea of a psychiatrist trying to understand the role of a single gene product in complex behavioral differences — after all, that is what he and his colleagues did in discovering and elucidating the molecular basis of fragile X syndrome.

Something that always stood out about Steve was his deep conviction that pursuing high-quality basic research is ultimately the most successful path to helping patients. He once pointed out to me that a single key scientific discovery could help many more patients than the efforts of even the most talented and dedicated individual clinician. That thirst to understand human disorders at their most fundamental molecular levels clearly drove Steve. What an inspiration he was to us all.

First and foremost, Steve was a brilliant scientist — co-discoverer not just of a disease gene, but of a genetic mechanism relevant to multiple disorders.

Steve had other talents that rivaled his powerful intellect and scientific prowess. His leadership skills immediately come to mind in this regard. As chair of human genetics, his desire to maximize the success and opportunities of his faculty was always apparent. I vividly remember my first faculty review meeting with him in 2005. He began the meeting with a simple question that literally reframed the discussion for me and showed me just how great a support he would always be for my professional development. He asked, “How can I be helpful to you?” That question, which directly conveyed his desire to help every one of his colleagues to excel, embodies how Steve approached his leadership role.

Finally, his personal qualities were remarkable. Born and raised in Detroit, Michigan, he was at his core a practical, honest, idealistic and altruistic Midwesterner. He approached the world with an eye to what was good and wholesome about it. He was always willing to help solve problems and support his faculty even in difficult times, and he always approached challenges in a fair-minded and good-humored way.

A few years back, I struggled through a prolonged period when none of my grant applications succeeded. Steve continued to support me, ensuring that my research time was protected so I could continue to pursue my scientific work and apply for funding. When in 2019 my colleagues and I finally did bring in substantial federal funding (to investigate the physiological and cellular aspects of risk for psychosis in a condition called 22q11 deletion syndrome), Steve was just so excited. I can remember his response to my telling him we had gotten the grant and thanking him for supporting me during lean times: “Joe, that is fantastic news!” He was genuinely thrilled at my success. That was Steve. The most inspiring chair under whom I have served in more than 40 years of working in the world of science.

I know I speak for every single person in my department, whether faculty, staff, student or postdoctoral researcher, when I say we miss him dearly and feel genuinely blessed to have known him.

Evan Eichler: Steve was a de-facto mentor over my entire career. I first met him as a graduate student in David Nelson’s laboratory at Baylor College Medicine in Houston, Texas, in the early 1990s. I arrived in the laboratory shortly after Steve and David had discovered the CGG triplet repeat expansion and its role in fragile X syndrome. Steve and David were close friends, and Steve very quickly became an unofficial mentor of mine who was instrumental in some of my early work as a student. He was sharp and scientifically rigorous, always getting quickly to the heart of the matter, and he was incredibly supportive.

What I remember most about Steve was his encouragement and grace in the face of rejection. When one of my first papers was ultimately rejected from Science after a couple of rounds of extensive revision (after Steve assuring me initially that it was a shoo-in), he remained upbeat, reminding me that the paper was still a great piece of work and would ultimately find a great home. His confidence and enthusiasm helped propel me forward and convinced me that I might actually make it as an independent investigator.

Many years later when he offered me a faculty position at Emory, which I ultimately declined, he once again demonstrated this same grace and a knack for uplifting — saying that he hoped that his offer could be leveraged to help me get a position elsewhere. While I didn’t immediately recognize it then, Steve was the epitome of a great mentor, chairman and scientist. He was an inspiration to so many who worked with him. While his early passing is a loss to the field of human genetics research, I personally will miss his advice, mentorship and friendship much more.

Clockwise from left: David Nelson, Huda Zoghbi, Harry Orr, Janelle Clark, Peng Jin, Steve Warren.

James Sutcliffe: I had the good fortune to be Steve’s first graduate student, arriving at Emory in the fall of 1986. Steve was a newly minted assistant professor in the Department of Biochemistry. He was a fantastic mentor, and it was fun being part of that group. Steve’s sense of humor was legend, and he loved telling stories. We went on frequent lab lunches and other adventures. I have vivid memories of the first paper we wrote together, and how my tortured first draft came back with so many red editor’s marks that the original text was unrecognizable. That experience, though, taught me how to write.

The period leading up to the fragile X site discovery was formative. After a few years of what felt like fumbling in the lab, my experiments began to work, and I felt like I was in command of what I was doing. One day I developed an X-ray film demonstrating how we had cloned the DNA flanking the fragile X site and breakpoints in the somatic cell hybrid lines Steve had developed. Steve was in Rotterdam, the Netherlands, visiting our collaborator, Ben Oostra, so I turned that blot into a figure and faxed it to them in Ben’s lab. (This was before email was common.) From that moment until the publication of the fragile X site and gene in Cell in 1991, our work was very intense and rewarding.

I also recall preparing my dissertation defense seminar, and how Steve advised me to “tell a story” in that seminar (and in subsequent postdoc interviews). It’s such simple advice, but it framed how to think about giving a good talk and was really useful for me at the time. I also remember that Steve had a way of helping others understand how the science world worked, and much of that came from funny stories he would tell about his own experiences. He reveled in the successes of his former trainees, and he really cared to know how you were doing and what was going on in your life

Huda Zoghbi: I got to know Steve through his collaboration with my Baylor colleagues David Nelson and Tom Caskey in their intense efforts to identify the gene behind fragile X syndrome.

Steve was a superb geneticist and biochemist, and he proceeded to study FMR1 and the protein it encodes, FMRP, at every level. His group showed that the large expansions cause a loss of function of the gene, and intermediate repeat expansions drive pathology by a gain-of-function mechanism. They showed that FMRP is an RNA-binding protein that governs the translation of many other proteins. Realizing that the field of neuroscience would both contribute to and learn from studies of fragile X, Steve made a concerted effort to draw neurobiologists as well as RNA biologists into the fold, particularly at several memorable meetings at the Howard Hughes Medical Institute in Chevy Chase, Maryland. He succeeded, in large part because he set a precedent for generosity in sharing ideas and reagents at a time when the field was extremely competitive and reagents were precious. Fruitful new collaborations revealed that the loss of FMRP leads to excessive glutamate signaling in neurons, paving the way for potential treatments.

Steve’s innate, rock-solid decency made him a respected and sought-after colleague. When you were with him, you received his undivided attention. He was an unassuming man who devoted tremendous energy to his work for the good of science. He continually brought out the best in his trainees and colleagues with his fairness, kindness and irresistible joie de vivre. When I served with him and other scientists as peer reviewer of federal grant applications, I looked forward to the meetings he led, because he kept the atmosphere stimulating, engaging and positive in a way that seemed effortless — rarely have I seen a group of tired, overworked scientists so relaxed and happy to be discussing grants! His kindly demeanor complemented a keen scientific mind, and this winning combination made him an effective and well-loved leader, whether in those grant-review panels, the American Society of Human Genetics or his department at Emory.

We will all miss him deeply, but we know his legacy will live on through his trainees and all the fragile X families he has helped through his scientific research, his leadership and his generosity as a human being.

Joseph Cubells is associate professor of human genetics at Emory University in Atlanta, Georgia. Evan Eichler is professor of genome sciences at the University of Washington in Seattle. James Sutcliffe is associate professor of molecular physiology and biophysics at Vanderbilt University in Nashville, Tennessee. Huda Zoghbi is professor of molecular and human genetics at Baylor College of Medicine, Howard Hughes Medical Institute Investigator and director of the Jan and Dan Duncan Neurological Research Institute in Houston, Texas.

Cite this article: https://doi.org/10.53053/JQKG1656

The post Remembering Steve Warren (1953-2021): A giant in the field of genetics appeared first on Spectrum | Autism Research News.